3-Amino-piperadine derivatives and methods of manufacture

ABSTRACT

This invention relates to 3-amino piperadine derivatives, their intermediates and methods of manufacture. As such, the present invention includes methods of making a compound of the formulas (Ia) and (Ib)  
                 
 
     wherein R 1 , R 2 , R 3 , R 4 , R 14 , and n are herein defined. The present invention also relates to the compounds used in such processes, as well as the compounds made by the processes.

RELATED APPLICATION

[0001] The present application claims priority to U.S. PatentApplication Serial No. 60/428,324, filed Nov. 21, 2002, which isincorporated herein in its entirety.

FIELD OF THE INVENTION

[0002] This invention relates to 3-amino-piperadine derivatives, theirintermediates, and methods of manufacture.

BACKGROUND

[0003] Pyrrolo[2,3-d]pyrimidine compounds are inhibitors of proteinkinases, such as the enzyme Janus Kinase 3 (JAK3) and are thereforeuseful therapy as immunosuppressive agents for organ transplants, xenotransplation, lupus, multiple sclerosis, rheumatoid arthritis,psoriasis, Type I diabetes and complications from diabetes, cancer,asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerativecolitis, Crohn's disease, Alzheimer's disease, Leukemia and otherindications where immunosuppression would be desirable. Thepyrrolo[2,3-d]pyrimidine compounds, pharmaceutical compositions thereofand methods of use are described in co-pending application Ser. No.09/732,669, filed Dec. 8, 2000, and assigned to the assignee of thepresent invention, which is incorporated herein by reference for allpurposes.

SUMMARY OF THE INVENTION

[0004] As embodied and broadly described herein, this invention, in oneaspect, relates to methods of making compounds of the formula (Ia)

[0005] wherein R₁ is carboxy, cyano, deuterium, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆) acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R₁₅R₁₆N—CO—O—, R₁₅R₁₆N—CO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(m),R₁₅R₁₆NS(O)_(m), R₁₅R₁₆NS(O)_(m) (C₁-C₆)alkyl, R₁₅S(O)_(m) R₁₆N,R₁₅S(O)_(m)R₁₆N(C₁-C₆)alkyl or a group of the formula (VII)

[0006] R₂ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl,(C₂-C₆)alkenyl, or (C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynylgroups are optionally substituted by deuterium, hydroxy,trifluoromethyl, (C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or(C₁-C₆)acylamino; or R₂ is (C₃-C₁₀)cycloalkyl wherein the cycloalkylgroup is optionally substituted by deuterium, hydroxy, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino;

[0007] R₃ is hydrogen, (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₂-C₆)alkenyl,or (C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, halogen, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, (C₁-C₆)acylamino,((C₁-C₆)alkyl)₂amino, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, ornitro(C₁-C₆)alkyl;

[0008] R₄ is (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₂-C₆)alkenyl, or(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, halogen, amino,trifluoromethyl, (C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino,(C₁-C₆)acylamino, ((C₁-C₆)alkyl)₂amino, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,cyano, cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, ornitro(C₁-C₆)alkyl;

[0009] R₆, R₇, R₈, R₉, R₁₀ and R₁ are each independently hydrogen or(C₁-C₆)alkyl optionally substituted by deuterium, hydroxy,trifluoromethyl, (C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R₁₂ is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)acyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂ amino,amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R₁₅R₁₆N—CO—O—, R₁₅R₁₆N—CO—(C₁-C₆)alkyl, R₁₅C(O)NH, R₁₅OC(O)NH,R₁₅NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m), (C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl,R₁₅R₁₆NS(O)_(m), R₁₅R₁₆NS(O)_(m) (C₁-C₆)alkyl, R₁₅S(O)_(m) R₁₆N, orR₁₅S(O)_(m)R₁₆N(C₁-C₆)alkyl;

[0010] R₁₅ and R₁₆ are each independently hydrogen or (C₁-C₆)alkyl;

[0011] X is S(O)_(p), oxygen, carbonyl or —C(═N-cyano)-;

[0012] Y is S(O)_(p) or carbonyl;

[0013] Z is S(O)_(p), carbonyl, C(O)O—, or C(O)NR—;

[0014] a is 0, 1, 2, 3 or 4;

[0015] b, c, e, f and g are each independently 0 or 1;

[0016] d is 0, 1, 2, or 3; m is 0, 1 or 2; n is 1, 2, 3, or 4; p is 0, 1or 2; and

[0017] wherein the method comprises reacting NHR₂R₃, N(CH₃)R₂H, orN(CH₂CH₃)R₂H with a compound of formula (IIa)

[0018] and reducing the compound so formed with a reducing agent. In oneembodiment, the reducing agent is a borohydride.

[0019] Moreover, the present invention relates to formation of thecompound of the formula (IIa) by reacting a compound having the formulaR₄OH, water, or R₄NH₂ and a compound of the formula (IIIa)

[0020] wherein R₅ is CO(C₁-C₆)alkyl.

[0021] The present invention further relates to formation of thecompound of the formula (IIa) by heating a compound having the formula(IVa)

[0022] with a compound having the formula(C₁-C₆)alkyl-(C═O)—O—(C═O)—(C₁-C₆)alkyl.

[0023] In addition, the present invention relates to formation of thecompound of the formula (IVa) by oxidizing a compound having the formula(Va)

[0024] under oxidizing conditions. In one embodiment, the oxidizingconditions are an electrochemical oxidation.

[0025] The present invention also relates to formation of the compoundof the formula (Va) by reacting a compound having the formula WCO₂R₄ anda compound having the formula (VIa)

[0026] wherein W is halogen.

[0027] A second aspect of the present invention relates to methods ofmaking a compound having the formula (Ib)

[0028] wherein R₁₃ is (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₆-C₁₀)aryl,(C₁-C₆)carboalkoxy, (C₅-Cg)heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl, or(C₅-Cg)heteroaryl(C₁-C₆)alkyl wherein the R₁₃ group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)alkyl,(C₁-C₄)alkoxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, trifluoromethyl(C₁-C₆)alkyl, nitro, or nitro(C₁-C₆); and

[0029] wherein the method comprises reducing a compound of formula (IIb)

[0030] with a reducing agent, wherein R₁₄ is (C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl wherein the alkyl,alkenyl and alkynyl groups are optionally substituted by deuterium,hydroxy, halogen, amino, trifluoromethyl, (C₁-C₄)alkoxy,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,trifluoromethyl(C₁-C₆)alkyl, nitro, or nitro(C₁-C₆)alkyl.,

[0031] The present invention also relates to formation of the compoundof the formula (IIb) by reacting a compound having the formula (IIIb)

[0032] with an aldehyde of formula R₁₃—(C═O)—H and reducing the compoundso formed with a reducing agent. In one embodiment, the reducing agentis lithium aluminum hydride.

[0033] Moreover, the present invention relates to formation of thecompound of the formula (IIIb) by hydrogenating a compound having theformula (IVb)

[0034] in the presence of a catalyst. In one embodiment, the catalyst isRh/alumina or Rh/C.

[0035] The present invention also relates to formation of the compoundof the formula (IVb) by reacting a compound having the formula (Vb)

[0036] with (R₁₄—O—(C═O))2O or R₁₄—O—(C═O)—X wherein X is halo.

[0037] Furthermore, in additional aspects, the present invention relatesto the compounds herein described including compounds of the formula(Ia), (Ib) and (IIb).

[0038] In some preferred embodiments of the methods and compounds ofaforementioned aspects of the present invention, R₁ is (C₁-C₆)alkyl andn is one; R₂ and R₃ are each hydrogen or (C₁-C₆)alkyl; R₄ is(C₁-C₆)alkyl; and/or R₁₃ is (C₆-C₁₀)aryl.

[0039] In one embodiment, the compound of formula (Ia) has the relativestereochemistry of formula (Ia-1)

[0040] In another embodiment, the compound of formula (Ib) has therelative stereochemistry of formula (Ib-1)

[0041] It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

[0042] The present invention may be understood more readily by referenceto the following detailed description of exemplary embodiments of theinvention and the examples included therein.

[0043] Before the present compounds and methods are disclosed anddescribed, it is to be understood that this invention is not limited tospecific synthetic methods of making that may of course vary. It is alsoto be understood that the terminology used herein is for the purpose ofdescribing particular embodiments only and is not intended to belimiting.

[0044] In this specification and in the claims that follow, referencewill be made to a number of terms that shall be defined to have thefollowing meanings:

[0045] Unless otherwise indicated, the alkyl and alkenyl groups referredto herein, as well as the alkyl moieties of other groups referred toherein (e.g., alkoxy), may be linear or branched, and they may also becyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl) or be linear or branched and contain cyclic moieties. Suchalkyl and alkoxy groups may be substituted with one, two or threehalogen and/or hydroxy atoms, preferably fluorine atoms.

[0046] Unless otherwise indicated, “halogen” and “halide” includesfluorine, chlorine, bromine, and iodine.

[0047] “(C₃-C₁₀)cycloalkyl” when used herein refers to cycloalkyl groupscontaining zero to two levels of unsaturation such as cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane,norbornanyl, and the like.

[0048] “(C₂-C₉)heterocycloalkyl” when used herein refers topyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl,pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, chromanyl, and the like. One ofordinary skill in the art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon or a Sp3 hybridizednitrogen heteroatom.

[0049] “(C₂-C₉)heteroaryl” when used herein refers to furyl, thienyl,thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl, and the like. One of ordinaryskill in the art will understand that the connection of said(C₂-Cg)heterocycloalkyl rings is through a carbon atom or a sp³hybridized nitrogen heteroatom.

[0050] “Aryl” when used herein refers to phenyl or naphthyl.

[0051] By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material may beadministered to an individual along with the selected compound withoutcausing any undesirable biological effects or interacting in adeleterious manner with any of the other components of thepharmaceutical composition in which it is contained.

[0052] The term “subject” is meant an individual. Preferably, thesubject is a mammal such as a primate, and more preferably, a human.Thus, the “subject” can include domesticated animals, livestock, andlaboratory animals.

[0053] In general, “effective amount” or “effective dose” means theamount needed to achieve the desired result or results (treating orpreventing the condition). One of ordinary skill in the art willrecognize that the potency and, therefore, an “effective amount” canvary for the various compounds used in the invention. One skilled in theart can readily assess the potency of the compounds.

[0054] Unless otherwise noted, numerical values described and claimedherein are approximate. Variation within the values may be attributed toequipment calibration, equipment errors, purity of the materials, amongother factors. Additionally, variation may be possible, while stillobtaining the same result.

[0055] The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated thesubstituents in the reaction Schemes and the discussion that follow aredefined as above.

[0056] In step 1 of Scheme 1, the compound of formula (VIa) is convertedto the carbamate of formula (Va) by reaction with a compound of formulaW—CO₂R₄ in a solvent system. The solvent system preferably contains anamine, such as triethylamine, diisopropylethylamine, or other tertiaryamine. Other solvents may also be used, including dichloromethane,tetrahydrofuran, and methyltetrahydrofuran. The mixture is then cooledto approximately −800 to 25° C. and the W—CO₂R₄ is slowly added tocontrol the temperature. The mixture is allowed to stir until for atleast one hour, preferably, four hours or more.

[0057] In step 2 of Scheme 1, the carbamate of formula (Va) is oxidizedto form the oxidation product (IVa). Typically, the oxidation reactionproduces a mixture of compounds having the formula (IVa). Any suitableoxidation conditions may be used. Preferred conditions includeelectrochemical oxidation, such as performing the oxidation reaction inan electrolytic solution in an electric cell and electrolyzing the cell.In one embodiment, the electrolytic solution is a mixture of acetic acidand potassium acetate. In another embodiment, the electrolytic solutionincludes acetic anhydride. The cathode and anode may be made of anysuitable material, including platinum and nioblum. The mixture is thenelectrolyzed at an appropriate current until the reaction issubstantially complete. The temperature of the electrolytic solution maybe maintained at a temperature lower than 60° C., preferably lower than40° C.

[0058] The oxidation product (IVa) is heated in step 3 of Scheme 1 witha compound having the formula (C₁-C₆)alkyl-(C═O)—O—(C═O)—(C₁-C₆)alkyl,including acetic anhydride, to produce the enamino acetate of formula(IIa). The temperature is preferably maintained at about 60° C. to about160° C.; more preferably, the temperature is raised to about >100° C.,more preferably to about >120° C. The mixture is allowed to stir for atleast two hours, preferably 4 hours or more.

[0059] In step 4 of Scheme 1, the enamino acetate (IIIa) is converted tothe ketopiperidine (IIa) by reaction with a compound having the formulaR₄OH, water or R₄NH₂. Preferably, this reaction is maintained attemperatures less than 20° C., more preferably less than 5° c.

[0060] In step 5 of Scheme 1, the ketopiperidine (IIa) is converted tothe aminopiperidine (Ia) by reaction with NHR₂R₃, N(CH₃)R₂R₃, orN(CH₂CH₃)R₂R₃. The product of this reaction is reduced with a reducingagent to form the aminopiperidine (Ia). The reactions are typicallyconducted in a solvent, such as methanol, at ambient temperature for atime period between about 12 hours to about 18 hours. Exemplary reducingagents include borohydrides, such as sodium cyanoborohydride and sodiumborohydride.

[0061] In step 1 of Scheme 2, the carbamate (IVb) is formed by reactingthe compound of formula (Vb) with a compound of the formula(R₁₄—O—(C═O))₂O or R₁₄—O—(C═O)—X wherein X is halo. Preferably, thetemperature is maintained below 0° C. The reaction is substantiallycomplete within minutes, usually within at least an hour.

[0062] In step 2 of Scheme 2, the carbamate (IVb) is hydrogenated toform the compound of formula (IIIb). The hydrogenation also may lead tocis-trans isomers. Certain catalysts may be desired for the cis:transselectivity. Exemplary hydrogentation catalysts include PtO₂, Rh/C(several types), RuO₂, Rh/Al₂O₃, Ru/C (several types), Lindlar'scatalyst, and Wilkinson's catalyst. Exemplary solvents include aceticacid, propanol, ethanol, methanol/ammonium hydroxide, acetonitrile,tetrahydrofuran, cyclohexane, heptanes, toluene, dimethylformamide,water. Generally, the temperature of the reaction is maintained aboveroom temperature, preferably above 60 C, and the pressure is increasedabove atmospheric pressure with hydrogen gas.

[0063] In step 3 of Scheme 2, the compound of formula (IIIb) is reactedwith an aldehyde of formula R₁₃—(C═O)—H and reduced with a reducingagent to form the compound (IIb). The reactions are typically conductedin a solvent, such as methanol, at ambient temperature for a time periodbetween about 12 hours to about 18 hours. Exemplary reducing agentsinclude borohydrides, such as sodium cyanoborohydride and sodiumborohydride. In one embodiment, the reducing agent istriacetoxyborohydride.

[0064] Finally, in step 4 of Scheme 2, the compound of formula (IIb) isreduced to the compound of formula (Ib). Exemplary reducing agentsinclude lithium aluminum hydride, Vitride (Red-Al), and borane. Thereduction is carried out in a solvent such as tetrahydrofuran,diethylether, or methyltetrahydrofuran, preferably at temperatures ofabout −10° to about 100° C. for about five minutes to about 48 hours.

[0065] In reactions A and B of Scheme 3, the compound of formula (Ia) or(Ib) as appropriate is coupled with a 4-chloro-pyrrolo[2,3-d]pyrimidinecompound of the formula (A):

[0066] wherein R′ and R″ are each independently selected from the groupconsisting of hydrogen, deuterium, amino, halo, hydoxy, nitro, carboxy,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, trifluoromethyl, trifluoromethoxy,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl wherein the alkyl,alkoxy or cycloalkyl groups are optionally substittued by one to threegroups selected from halo, hydroxy, carboxy, amino (C₁-C₆)alkylthio,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₅-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl, (C₃-C₉)cycloalkyl or (C₆-C₁₀)aryl; or R² and R³are each independently (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkoxy,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino,(C₁-C₆)alkylthio, (C₆-C₁₀)arylthio, (C₁-C₆)alkylsulfinyl,(C₆-C₁₀)arylsulfinyl, (C₁-C₆)alkylsulfonyl, (C₆-C₁₀)arylsulfonyl,(C₁-C₆)acyl, (C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyamino-CO—,(C₅-Cg)heteroaryl, (C₂-Cg)heterocycloalkyl or (C₆-C₁₀)aryl wherein theheteroaryl, heterocycloalkyl and aryl groups are optionally substitutedby one to three halo, (C₁-C₆)alkyl, (C₁-C₆)alkyl-CO—NH—,(C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkoxy,carboxy, carboxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkoxy,benzyloxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy,(C₆-C₁₀)aryl, amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonylamino,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, carboxy,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—,(C₁-C₆)alkyl-CO—NH—, cyano, (C₅-Cg)heterocycloalkyl, amino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—, ((C₁-C₆)alkyl)₂amino-CO—NH—,(C₆-C₁₀)arylamino-CO—NH—, (C₅-Cg)heteroarylamino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino-CO—NH—(C₁-C₆)alkyl,(C₆-C₁₀)arylamino-CO—NH—(C₁-C₆)alkyl,(C₅-Cg)heteroarylamino-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl,(C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₆-C₁₀)arylsulfonyl, (C₆-C₁₀)arylsulfonylamino,(C₆-C₁₀)arylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₅-Cg)heteroaryl and(C₂-Cg)heterocycloalkyl; and

[0067] R′″ is hydrogen or a protecting group;

[0068] to create the 4-aminopyrrolo[2,3-d]pyrimidine compound of formula(I), wherein R is R₄-O—(C═O)— or R₁₃—(CH₂)—.

[0069] The coupling reaction is carried out in an alcohol solvent, suchas tert-butanol, methanol or ethanol, or other high boiling organicsolvents, such as dimethylformamide, triethylamine, 1,4-dioxane or1,2-dichloroethane, at a temperature between about 60° C. to about 120°C., preferably about 80° C. Typical reaction times are between about 2hours to about 48 hours, preferably about 16 hours.

[0070] If R′″ is a protecting group, the protecting group may be removedin an additional step. For example, removal of the protecting group,wherein R′″ is benzenesulfonyl, is carried out by treating the productof the coupling reaction A or B with an alkali base, such as sodiumhydroxide or potassium hydroxide, in an alcohol solvent, such asmethanol or ethanol, or mixed solvents, such as alcohol/tetrahydrofuranor alcohol/water. The reaction is carried out at room temperature for atime period between about 15 minutes to about 1 hour, preferably 30minutes. Removal of the protecting group, wherein R is benzyl, isconducted by treating the product of the coupling reaction A or B withsodium in amrionia at a temperature of about −78° C. for a time periodbetween about 15 minutes to about 1 hour.

[0071] Unless indicated otherwise, the pressure of each of the abovereactions is not critical. Generally, the reactions are conducted at apressure of about one to about three atmospheres, preferably at ambientpressure (about one atmosphere).

[0072] The compounds of the formulas (Ia) and (Ib) are capable offorming a wide variety of different salts with various inorganic andorganic acids.

[0073] The compounds of the present invention that are basic in natureare capable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate the compound of the presentinvention from the reaction mixture as a pharmaceutically unacceptablesalt and then simply convert the latter back to the free base compoundby treatment with an alkaline reagent and subsequently convert thelatter free base to a pharmaceutically acceptable acid addition salt.The acid addition salts of the base compounds of this invention arereadily prepared by treating the base compound with a substantiallyequivalent amount of the chosen mineral or organic acid in an aqueoussolvent medium or in a suitable organic solvent, such as acetone,methanol or ethanol. Upon careful evaporation of the solvent, thedesired solid salt is readily obtained. The desired acid salt can alsobe precipitated from a solution of the free base in an organic solventby adding to the solution an appropriate mineral or organic acid.

[0074] Those compounds of the present invention that are acidic innature, are capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the calcium, sodium andpotassium salts. These salts are all prepared by conventionaltechniques. The chemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of the presentinvention. Such non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

[0075] The compounds of the present invention are important in themanufacture of compound of the formula I (wherein the substituents areas previously defined):

[0076] The compounds of the formula I and its pharmaceuticallyacceptable salts (hereinafter also referred to, collectively, as “theactive compounds”) are inhibitors of protein kinases, such as the enzymeJanus Kinase 3 (JAK3) and are therefore useful therapy asimmunosuppressive agents for treating or preventing organ transplantrejection, xeno transplation; lupus, multiple sclerosis, rheumatoidarthritis, psoriasis, Type I diabetes and complications from diabetes,cancer, asthma, atopic dermatitis, autoimmune thyroid disorders,ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia andother autoimmune diseases, acute and chronic organ transplant rejection,heart transplant rejection, lung transplant rejection, liver transplantrejection, kidney transplant rejection, pancreas transplant rejection,uterus transplant rejection, joints transplant rejection, isletstransplant rejection, bone marrow transplant rejection, limb transplantrejection, cornea transplant rejection, skin transplant rejection,hepatocytes transplant rejection, hepatocytes cell transplant rejection,pancreatic beta-cells transplant rejection, stem cell transplantrejection, neural cell transplant rejection, cardiac myocytes celltransplant rejection, immune-related infertility, HIV replicationsuppression, Hepatitis B, Hepatitis C, interstitial cystitis, primarybiliary cirrhosis, psoriasis, psoriatic arthritis, and juvenilearthritis in a mammal, including a human,

[0077] The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation. The activecompounds of the invention may also be formulated for sustaineddelivery.

[0078] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e., lactose, microcrystalline cellulose orcalcium phosphate); lubricants (eq., magnesium stearate, talc orsilica); disintegrants (eq., potato starch or sodium starch glycolate);or wetting agents (e., sodium lauryl sulphate). The tablets may becoated by methods well known in the art. Liquid preparations for oraladministration may take the form of, for example, solutions, syrups orsuspensions, or they may be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations may be prepared by conventional means with pharmaceuticallyacceptable additives such as suspending agents (e.g., sorbitol syrup,methyl cellulose or hydrogenated edible fats); emulsifying agents (eq.,lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily estersor ethyl alcohol); and preservatives (eq., methyl or propylp-hydroxybenzoates or sorbic acid).

[0079] For buccal administration, the composition may take the form oftablets or lozenges formulated in conventional manner.

[0080] The active compounds of the invention may be formulated forparenteral administration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

[0081] The active compounds of the invention may also be formulated inrectal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides.

[0082] For intranasal administration or administration by inhalation,the active compounds of the invention are conveniently delivered in theform of a solution or suspension from a pump spray container that issqueezed or pumped by the patient or as an aerosol spray:presentationfrom a pressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

[0083] A proposed dose of the active compounds of the invention fororal, parenteral or buccal administration to the average adult human forthe treatment of the conditions referred to above (eq., rheumatoidarthritis) is 0.1 to 1000 mg of the active ingredient per unit dosewhich could be administered, for example, 1 to 4 times per day.

[0084] Aerosol formulations for treatment of the conditions referred toabove (e., asthma) in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains 20 μg to 1000 μg ofthe compound of the invention. The overall daily dose with an aerosolwill be within the range 0.1 mg to 1000 mg. Administration may beseveral times daily, for example 2, 3, 4 or 8 times, giving for example,1, 2 or 3 doses each time.

[0085] The active compounds of formula (Ia-1) administered in apharmaceutically acceptable form either alone or in combination with oneor more additional agents which modulate a mammlian immune system orwith antiinflammatory agents, agents which may include but are notlimited to cyclosporin A (e.g. Sandimmune® or Neoral®, rapamycin, FK-506(tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g.Cellcept®, azathioprine (e.g. Imuran®), daclizumab (e.g. Zenapax®), OKT3(e.g. Orthocolone®), AtGam, aspirin, acctaminophen, ibuprofen, naproxen,piroxicam, and antiinflmmatory steroids (e.g. prednisolone ordexamethasone), an EPO, FK 778, Sdz-rad, steroids, IVIG, COX-2inhibitor, NSAIDS, FTY720, basiliximab, donor cells, enerolimus,anti-CD28/CTLA41g, ISTA-TX-247, gancyciovir, interferon and alpha/rebif,septra, anti-TNFS, P38 inhibitors, CCR₁ antagonists, PDE4 antagonists,lipitor/statins, acyclovir, ribovikin, protease inhibitors/RTis,insulin, rituximab, cetirizine or Hi blockers; and such agents may beadministered as part of the same or separate dosage forms, via the sameor different routes of administration, and on the same or differentadministration schedules according to standard pharmaceutical practice.

[0086] FK506 (Tacrolimus) is given orally at 0.10-0.15 mg/kg bodyweight, every 12 hours, within first 48 hours postoperative. Dose ismonitored by serum Tacrolimus trough levels.

[0087] Cyclosporin A (Sandimmune oral or intravenous formulation, orNeoralb, oral solution or capsules) is given orally at 5 mg/kg bodyweight, every 12 hours within 48 hours postoperative. Dose is monitoredby blood Cyclosporin A trough levels.

[0088] The active agents can be formulated for sustained deliveryaccording to methods well known to those of ordinary skill in the art.Examples of such formulations can be found in U.S. Pat. Nos. 3,538,214,4,060,598, 4,173,626, 3,119,742, and 3,492,397.

[0089] The ability of the compounds of formula I or theirpharmaceutically acceptable salts to inhibit Janus Kinase 3 and,consequently, demonstrate their effectiveness for treating disorders orconditions characterized by Janus Kinase 3 is shown by the following invitro assay tests.

Biological Assay JAK3 (JH1:GST) Enzvmatic Assay

[0090] The JAK3 kinase assay utilizes a protein expressed inbaculovirus-infected SF9 cells (a fusion protein of GST and thecatalytic domain of human JAK3) purified by affinity chromatography onglutathione-Sepaharose. The substrate for the reaction is poly-Glutamicacid-Tyrosine (PGT (4:1), Sigma catalog # PO₂₇₅), coated onto Nunc MaxiSorp plates at 100 μg/ml overnight at 37° C. The morning after coating,the plates are washed three times and JAK3 is added to the wellscontaining 100 μl of kinase buffer (50 mM HEPES, pH 7.3, 125 mM NaCl, 24mM MgC12)+0.2 uM ATP+1 mM Na orthovanadate.) The reaction proceeds for30 minutes at room temperature and the plates is washed three moretimes. The level of phosphorylated tyrosine in a given well isquantitated by standard ELISA assay utilizing an anti-phosphotyrosineantibody (ICN PY20, cat. #69-151-1).

Inhibition of Human IL-2 Dependent T-Cell Blast Proliferation

[0091] This screen measures the inhibitory effect of compounds on IL-2dependent T-Cell blast proliferation in vitro. Since signaling throughthe IL-2 receptor requires JAK-3, cell active inhibitors of JAK-3 shouldinhibit IL-2 dependent T-Cell blast proliferation.

[0092] The cells for this assay are isolated from fresh human blood.After separation of the mononuclear cells using AccuspinSystem-Histopaque-1077 (Sigma # A7054), primary human T-Cells areisolated by negative selection using Lympho-Kwik T (One Lambda, Inc.,Cat # LK-50T). T-Cells are cultured at 1−2×10⁶/ml in Media (RPMI+10%heat-inactivated fetal calf serum (Hyclone Cat # A-1111-L)+1%Penicillin/Streptomycin (Gibco)) and induce to proliferate by theaddition of 10 ug/ml PHA (Murex Diagnostics, Cat # HA 16). After 3 daysat 37° C. in 5% CO₂, cells are washed 3 times in Media, resuspended to adensity of 1−2×10⁶ cells/ml in Media plus 100 Units/ml of humanrecombinant IL-2 (R&D Systems, Cat # 202-IL). After 1 week the cells areIL-2 dependent and can be maintained for up to 3 weeks by feeding twiceweekly with equal volumes of Media +100 Units/ml of IL-2.

[0093] To assay for a test compounds ability to inhibit IL-2 dependentT-Cell proliferation, IL-2 dependent cells are washed 3 times,resuspended in media and then plated (50,000 cells/well/0.1 ml) in aFlat-bottom 96-well microtiterplate (Falcon # 353075). From a10 mM stockof test compound in DMSO, serial 2-fold dilutions of compound are addedin triplicate wells starting at 10 uM. After one hour, 10 Units/ml ofIL-2 is added to each test well. Plates are then incubated at 37° C., 5%CO₂ for 72 hours. Plates are then pulsed with ³H-thymidine (0.5uCi/well) (NEN Cat # NET-027A), and incubated an additional 18 hours.Culture plates are then harvested with a 96-well plate harvester and theamount of ³H-thymidine incorporated into proliferating cells isdetermined by counting on a Packard Top Count scintillation counter.Data is analyzed by plotting the % inhibition of proliferation versesthe concentration of test compound. An IC₅₀ value (uM) is determinedfrom this plot.

[0094] Experimental

[0095] The following examples are put forth so as to provide those ofordinary skill in the art with a complete disclosure and description ofhow the compounds, compositions, and methods claimed herein are made andevaluated, and are intended to be purely exemplary of the invention andare not intended to limit the scope of what the inventors regard astheir invention. Unless indicated otherwise, percent is percent byweight given the component and the total weight of the composition,temperature is in OC or is at ambient temperature, and pressure is at ornear atmospheric. Commercial reagents were utilized without furtherpurification. The following abbreviations are herein used:

[0096] AA is amino acid

[0097] AcOH is acetic acid

[0098] Boc is t-butoxy carbonyl

[0099] CDCl₃ is deuteriotrichloromethane

[0100] DMF is N,N-dimethylformamide

[0101] EtOAc is ethyl acetate

[0102] HCl is hydrochloric acid

[0103] HMDS is hexamethyldisilazane

[0104] IPE is isopropyl ether

[0105] MeOH is methanol

[0106] THF is tetrahydrofuran

[0107] g is grams

[0108] L is liter

[0109] M is molar

[0110] ml is milliliter

[0111] mmol is millimole

[0112] MHz is mega hertz

[0113] N is normal

[0114] psi is pounds per square inch

[0115] h is hours

[0116] min is minutes

[0117] sec is seconds

[0118] mp is melting point

[0119] RT is room temperature

[0120] Vacuo is in vacuum

[0121] ˜ is roughly approximate to*

[0122] HPLC is high pressure liquid chromatography

[0123] LCMS is liquid chromatograph mass spectrometer

[0124] NMR is nuclear magnetic resonance

[0125] TLC is thin layer chromatography

EXAMPLE 1 Cis-(1-Benzyl-4-methyl-piperidin-3-yl)-methyl-amineHydrochloride Salt

[0126] (4-Methyl-pyridin-3-yl)-carbamic Acid Methyl Ester

[0127] The synthesis was carried out by charging 2 grams (1 equiv., 18.5mmol) 4-Methyl-pyridin-3-ylamine to a solution of 6.55 grams potassiumt-butoxide (3 equiv., 55.5 mmol) in 10 ml THF (6.66 euiv., 123 mmol) at0° C. Upon anion formation, 2.34 ml dimethyl carbonate (1.5 equiv., 27.7mmol) were charged to the reaction at a rate so that the temperaturestayed below 0° C. The reaction was complete within 30 minutes and thered slurry was quenched with 50 ml water (25 volumes) and extracted in50 ml ethyl acetate (25 volumes). The aqueous layer was extracted with50 ml ethyl acetate (25 volumes) and then the orange organic layers wereconcentrated to an orange solid. NMR data showed that t-butanol existedin the product so the solids were slurried in 10 ml toluene (5 volumes)and then concentrated to dryness. This operation was performed threetimes in order to give very clean light orange solids. (89% yield). ¹HNMR: 88.90 (1H, brs), 8.28 (1H, d, J=4.8), 7.16-7.14 (1H, m), 6.54 (1H,brs), 3.80 (3H, s), 2.29 (3H, s).

[0128] Cis-(4-Methyl-piperidin-3-yl)-carbamic Acid Methyl Ester

[0129] The hydrogenation was carried out by charging 5 grams (1 equiv.,30.1 mmol) (4-methyl-pyridin-3-yl)-carbamic acid methyl ester, 50 mlethanol (10 volumes), and 2.5 grams rhodium on alumina (0.5 wt. equivs.)to a bomb hydrogenator. The hydrogenation was performed under 100 psihydrogen at 100° C. for 24 hours to give onlycis-(4-methyl-piperidin-3-yl)-carbamic acid methyl ester and its transisomer (5:1 ratio) in quantitative yield. ¹H NMR: δ5.6 (1H, d, J=8.4Hz), 3.66 (1H, d, J=3.6 Hz), 3.65-3.57 (3 H, brs), 3.1 (2H, d, J=9.6,minor isomer), 2.91-2.86 (2H, m), 2.67-2.64 (1H, m), 2.54-2.43 (1H, m),2.2-1.9 (1H, m, minor isomer), 1.78-1.65 (5H, brs, minor isomer),1.65-1.59 (4H, m, minor isomer), 1.36-1.25 (2H, m), 1.24-1.13 (2H, m),0.92 (3H, d, J=6.8 Hz, minor isomer), 0.83 (3H, d, J=7.2).

[0130] Cis-(1-Benzyl-4-methyl-piperidin-3-yl)-carbamic Acid Methyl Ester

[0131] The reductive amination of cis-(4-methyl-piperidin-3-yl)-carbamicacid methyl ester was carried out by charging 3.9 grams (1 equiv., 22.6mmol) to 2.07 ml benzaldehyde (0.9 equiv., 20.4 mmol), 9.6 grams sodiumtriacetoxyborohydride (2 equivs., 45.3 mmol) and 39 ml methylenechloride (10 volumes). The reaction was stirred at 20° C. and wasallowed to exotherm to 30°-35° C. The reaction was complete by GCMSwithin 30 minutes. The reaction was quenched with 78 ml saturated sodiumbicarbonate (20 volumes), extracted into 78 ml methylene chloride (20volumes) and concentrated to a clear oil. (70% yield). ¹H NMR: δ7.2-7.3(5H, m, aromatic protons), 5.50-5.48 (1H, d, J=8.8 Hz), 3.77-3.75 (1H,d, J=8.0 Hz), 3.63 (3H, s), 3.45-3.38 (2H, m), 2.77-2.74 (2H, d, J=11.2Hz), 2.14-2.01 (1H, m), 1.94-1.89 (1 H, m), 1.57-1.55 (1H, brs),1.37-1.20 (2H, m), 0.876 (3H, d, J=9.2 Hz).

[0132] (1-Benzyl-4-methyl-piperidin-3-yl)-methyl-amine

[0133] The reduction of cis-(1-benzyl-4-methyl-piperidin-3-yl)-carbamicacid methyl ester was performed by charging 2 grams substrate (1 equiv.,7.62 mmol) to a solution of 20 ml THF (10 volumes) and 15.2 ml 1 M LAHin THF (2 equiv., 15.2 mmol). The addition was performed at a rate sothat the temperature reached 30°-40° C. and then the reaction wasallowed to cool to 20° C. The reaction was worked up by quenching with40 ml Rochelle Salt (20 volumes) to a temperature of 35° C. and thenextracting the product 2 times into 20 ml methylene chloride (10volumes). The filtrate was then concentrated to a clear and colorlessoil. (90% yield). Note that the starting material needs to be clean inorder for this reaction to proceed in high yield.

[0134]¹H NMR: δ7.2-7.3 (5H, m, aromatic protons), 3.54-3.51 (1H, d,J=13.6), 3.40-3.37 (1H, d, J=13.6), 2.70-2.62 (2H, m), 2.39-2.36 (1H,brs) 2.32 (3H, s), 2.29-2.12 (1H, brs), 2.1.0-2.00 (1H, brs), 1.66 (1H,brs), 1.47-1.43 (2H, m), 1.32 (1H, brs), 0.936-0.919 (3H, d, J=6.8).

[0135] Cis-(1-Benzyl-4-methyl-piperidin-3-yl)-methyl-amine HydrochlorideSalt

[0136] The final salt formation was performed by charging 1.5 gramscis-(1-benzyl-4-methyl-piperidin-3-yl)-methyl-amine (1 equiv., 5.15mmol) and 4.5 ml ethanol (3 volumes) to a reactor at 0° C. To the 0° C.pot, was charged 0.93 ml 36% HCl (0.625 volumes) so that the temperaturestayed below 10° C. Next 3 mis ethanol (2 volumes) were concentratedfrom the reaction. To the reaction was charged 7.5 mls ethyl acetate (5volumes), the reaction was stirred for 5 minutes and then 6 mls ethylacetate (4 volumes) were removed in vacuo. 7.5 mls ethyl acetate (5volumes) were again charged and the concentration was again performed.Next, 4.5 mls acetone (3 volumes) were added and the reaction was slowlycooled to 0° C. in order to afford white solids. (37.5% yield). ¹H NMR:δ7.78-7.76 (2H, d, J=8.0 Hz), 7.29-7.18 (5H, m, aromatic protons), 5.55(1H, s), 3.45-3.41 (1H, d, J=13.2 Hz), 3.39-3.36 (1H, d, J=13.2 Hz),2.79 (1H, brs), 2.63 (1 H, brs), 2.45 (3H, s), 2.30 (2H, s), 2.25-2.05(1H, m), 1.76 (1H, brs), 1.40-1.39 (2H, m), 0.875-0.845 (3H, d, J=12).

EXAMPLE 2 4-Methyl-3-methylamino-piperidine-1-carboxylic Acid MethylEster

[0137] 4-Methyl-piperidine-1-carboxylic Acid Methyl Ester

[0138] To a three neck round bottom flask was added 360 g of4-methylpiperdine, 470 mL of triethylamine, and 390 mL of methylenechloride and the mixture was cooled in an ice bath. To this mixture wasadded methylchloroformate (260 mL) in methylene chloride (215 mL) slowlyto maintain a reaction temperature of 20 C or below. The reaction wasstirred overnight, then 200 mL of water was added and the layers wereseparated. The organic layer was washed with dilute HCl, satd. NaHCO3,and brine, and then the organic layer was dried over sodium sulfate andthe solvent was removed in vacuo. The product was distilled at 90-93 Cat 10 mm pressure to provide 338 g of product.

[0139] Mixture of 2,3-Diacetoxy-4-methyl-piperidine-1-carboxylic AcidMethyl Ester and 3-Acetoxy-2-hydroxy-4-methyl-piperidine-1-carboxylicAcid

[0140] In a 500 mL undivided glass cell equipped with a 60 cm² Pt meshanode and a Pt-clad Nb mesh cathode. A polypropylene mesh separator wasplaced between the electrodes. To the cell was charged 50 g of4-Methyl-piperidine-1-carboxylic acid methyl ester, 40 g of KOAc, and320 mL of HOAc. The mixture was electrolyzed at a constant current of6.0A until 20 F/mol was passed through the mixture. The cell voltagevaried between 13.5V and 20V. The reaction was immersed in a cold waterbath to maintain the reaction temperature around 35-40 C. The crudemixture of 2,3-Diacetoxy-4-methyl-piperidine-1-carboxylic acid methylester and 3-Acetoxy-2-hydroxy-4-methyl-piperidine-1-carboxylic acidmethyl ester was carried into the next step.

[0141] 5-Acetoxy-4-methyl-3,4-dihydro-2H-pyridine-1-carboxylic AcidMethyl Ester

[0142] 101.9 g (0.649 mol) of the mixture of2,3-diacetoxy-4-methyl-piperidine-1-carboxylic acid methyl ester and3-acetoxy-2-hydroxy-4-methyl-piperidine-1-carboxylic acid, wasconcentrated under reduced pressure until a solid formed. The solid wasthen added to a 2 L round bottom flask equipped with a nitrogen outlet,condenser and thermocouple. To this mixture was added acetic anhydride(430 ml) and then refluxed at 141° C. for two hours. The solution wasstirred overnight at room temperature. Most of the acetic anhydride wasremoved under reduced pressure and the remaining amount was removed byadding H₂O (400 ml) and a 5% solution of NaHCO₃ until the pH>7. Theaqueous mixture was extracted with ethyl acetate (3×250 ml), the organiclayers were combined and the ethyl acetate was removed under reducedpressure. Approximately 119.0 g of a thick brown oil material5-acetoxy-4-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid methylester was recovered. The TLC indicates conversion to product5-acetoxy-4-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid methylester as the major component. The material was split evenly into twoportions for separate hydrolysis reactions.

[0143] 4-Methyl-3-oxo-piperidine-1-carboxylic Acid Methyl Ester(Hydrolysis Using Dimethylamine):

[0144] In a 1 L flask, 60 g of crude product5-acetoxy-4-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid methylester was dissolved in 100 ml of MeOH and 40 g (0.325 mol) of 40%dimethylamine in methanol was added over 15 min at 0° C. The, mixturewas left to stir under nitrogen at room temperature overnight. The TLCshowed product 4-Methyl-3-oxo-piperidine-1-carboxylic acid methyl esterwas formed as the major component. The methanol solution was removedunder reduced pressure and the residue was extracted withdichloromethane (3×100 mL). The dichloromethane layer was washed withwater (3×50 ml) and the organic layer was separated and the solventremoved under reduced pressure. The crude residue was purified by columnchromatography.

[0145] The product was purified on silica gel column′ (360 g). Elutionwith hexane/ethyl acetate mixture 70:30 (5 L) furnished non-polarbyproducts. Continued elution with the same solvent mixture (6 L)followed by hexane/ethyl acetate 50:50 (3 L) furnished compound4-Methyl-3-oxo-piperidine-1-carboxylic acid methyl ester as an oil afterthe solvents were removed under vacuum. Yield: 11.9 g (0.0696 mol, 27%),TLC (SiO₂, ethyl acetate/hexane 1:1) and NMR

[0146] 4-Methyl-3-oxo-piperidine-1-carboxylic Acid Methyl Ester(Synthesis with Sodium Carbonate/Sodium Bicarbonate Buffer):

[0147] In a 1000 ml round bottom flask, 50 g of crude5-acetoxy-4-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid methylester was dissolved in 200 ml of methanol. To 300 ml water was added 30g of sodium carbonate and 30 g sodium bicarbonate (pH=10). The aqueousbuffer was added to the methanol solution. Methanol was added to themixture until it stirred easily, and stirred at room temperature for 18hours. The mixture was then concentrated to remove methanol. Water wasadded to the mixture to dissolve all salts. This was then extracted withethyl acetate three times. The organic extracts were combined, driedover magnesium sulfate, filtered, and evaporated to furnish the crudecompound 4-Methyl-3-oxo-piperidine-1-carboxylic acid methyl ester asoil, which was then purified as described below.

[0148] The resulting oil was split in half, and 26.9 g was run down asilica gel column using 350 ml of silica gel. The solvent was eluted asa gradient starting at 5% ethyl acetate in hexanes. The product waseluted with 10% ethyl acetate. Fractions showing pure product in TLC(SiO₂, Ethyl acetate/hexane 1:1) were combined and concentrated toafford 8.85 g (32% yield). Further fractions showing product with minorimpurities in TLC were combined and concentrated. Additional material(3.2 g, 10%) slightly less pure was also isolated.

[0149] The remaining half of the crude product (26.9 g) was distilled inhigh vacuum. Fractions boiling at 99-100° C./1 mm was collected. Weight12.1 g (yield, 41%). The material compared in TLC and NMR with thesample purified by chromatography but had minor non-polar impuritiesaccording to TLC (SiO₂, Ethyl acetate/hexane 1:1).

[0150] 4-Methyl-3-methylamino-Diieridine-1-carboxylic Acid Methyl Ester(Synthesized with Methylamine/Sodium Cyanoborohydride)

[0151] In a 100 ml round bottom flask, 4 g of impure4-Methyl-3-oxo-piperidine-1-carboxylic acid methyl ester was dissolvedin 20 ml methanol. To the stirring mixture was added 2M methylamine (25ml in methanol solution). After 1 hour of stirring at room temperature,sodium cyanoborohydride, (0.7 g) was added, and stirred for 3 days. Toquench the reaction, water (10 ml) was added with strong stirring, andthen concentrated HCl was slowly added until the pH was strongly acidic(pH=˜1), and remained acidic. After 2 hours, the mixture wasconcentrated, and the aqueous solution extracted twice with methylenechloride. The organic extracts were combined, dried over magnesiumsulfate, filtered, and evaporated. The residue was run down a silica gelcolumn with a gradient of 50% ethyl acetate in hexane, and ending with100% methanol. Weight of material is 600 mg. NMR (CDCl₃) revealed thatthe desired compound 4-Methyl-3-methylamino-piperidine-1-carboxylic acidmethyl ester was formed as a mixture of diastereomeric isomers. Theratio of the mixtures was approximately 1:1 from the splitting of the4-methyl group. IR does show a C═O stretching for the carbamate.

[0152] 4-Methyl-3-methylamino-Piperidine-1-carboxylic Acid Methyl Ester(Synthesized with Methylamine/Sodium Borohydride)

[0153] In a 50 ml round bottom flask, 2.0 g of the ketone4-Methyl-3-oxo-piperidine-1-carboxylic acid methyl ester was dissolvedin 6.0 ml of 2M methylamine in methanol. This solution was stirred for 1hour, after which it was concentrated by rotary evaporation. In aseparate 100 ml round bottom flask, 0.6 g sodium borohydride was addedto 6 ml dry tetrahydrofuran under an argon atmosphere, and cooled in anice bath. To the suspension, 3.6 ml glacial acetic acid was slowly addedwith stirring and continued cooling. The methylamine-ketone solutionfrom above was diluted in absolute ethanol, and slowly added to thesodium borohydride solution with continued cooling in an ice bath. Afteraddition was completed (ca. 1 hr), the mixture was allowed to warm toroom temp. After 2 hours the flask was stored at 4° C. overnight. To thestirring solution was added 10 ml of water. After 20 minutes,concentrated hydrochloric acid was slowly added until the pH remainedaround 2. The mixture was then concentrated by rotary evaporation. Theaqueous solution was made basic with sodium carbonate, and extractedthree times with ethyl acetate. The organic layers were combined, driedover magnesium sulfate, filtered and concentrated by rotary evaporation.The oil was purified using a silica gel column with a solvent consistingof 1% ammonium hydroxide solution, 3% methanol in methylene chloride.Fractions showing the product were combined and solvent removed byrotary evaporation. Weight of product was 400 mg (18.5% yield). TLCcompares with compound 4-Methyl-3-methylamino-piperidine-1-carboxylicacid methyl ester prepared by the other route.

[0154] Throughout this application, various publications are referenced.The disclosures of these publications in their entireties are herebyincorporated by reference into this application for all purposes.

[0155] It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A method of making a compound of formula (Ia)

wherein R₁ is carboxy, cyano, deuterium, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl,(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro, cyano(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl,trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R₁₅R₁₆N—CO—O—, R₁₅R₁₆N—CO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(m),R₁₅R₁₆NS(O)_(m), R₁₅R₁₆NS(O)_(m) (C₁-C₆)alkyl, R₁₅S(O)_(m) R₁₆N,R₁₅S(O)_(m)R₁₆N(C₁-C₆)alkyl or a group of the formula (VII)

R₂ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl, or(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R₂is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino; R₃ is hydrogen, (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₆)alkenyl, or (C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynylgroups are optionally substituted by deuterium, hydroxy, halogen,trifluoromethyl, (C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino,(C₁-C₆)acylamino, ((C₁-C₆)alkyl)₂amino, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,cyano, cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, ornitro(C₁-C₆)alkyl; R₄ is (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₆)alkenyl, or (C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynylgroups are optionally substituted by deuterium, hydroxy, halogen, amino,trifluoromethyl, (C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino,(C₁-C₆)acylamino, ((C₁-C₆)alkyl)₂amino, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,cyano, cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, ornitro(C₁-C₆)alkyl; R₆, R₇, R₃, R₉, R₁₀ and R₁₁ are each independentlyhydrogen or (C₁-C₆)alkyl optionally substituted by deuterium, hydroxy,trifluoromethyl, (C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R₁₂ is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)acyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂ amino,amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R₁₅R₁₆N—CO—O—, R₁₅R₁₆N—CO—(C₁-C₆)alkyl, R₁₅C(O)NH, R₁₅OC(O)NH,R₁₅NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m), (C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl,R₁₅R₁₆NS(O)_(m), R₁₅R₁₆NS(O)_(m) (C₁-C₆)alkyl, R₁₅S(O)_(m) R₁₆N, orR₁₅S(O)_(m)R₁₆N(C₁-C₆)alkyl; R₁₅ and R₁₆ are each independently hydrogenor (C₁-C₆)alkyl; X is S(O)_(p), oxygen, carbonyl or —C(═N-cyano)-; Y isS(O)_(p) or carbonyl; Z is S(O)_(p), carbonyl, C(O)O—, or C(O)NR—; a is0, 1, 2, 3 or 4; b, c, e, f and′ g are each independently 0 or 1; d is0, 1, 2, or 3; m is 0, 1 or 2; n is 1, 2, 3, or 4; p is 0, 1 or 2; andwherein the method comprises reacting NHR₂R₃, N(CH₃)R₂H, or N(CH₂CH₃)R₂Hwith a compound of formula (IIa)

and reducing the compound so formed with a reducing agent.
 2. The methodof claim 1, wherein the method further comprises formation of thecompound of the formula (IIa) by reacting a compound having the formulaR₄OH, water, or R₄NH₂ and a compound of the formula (IIIa)

wherein R₅ is CO(C₁-C₆)alkyl.
 3. The method of claim 2, wherein themethod further comprises formation of the compound of the formula (IIIa)by heating a compound having the formula (IVa)

with a compound having the formula(C₁-C₆)alkyl-(C═O)—O—(C═O)—(C₁-C₆)alkyl.
 4. The method of claim 3,wherein the method further comprises formation of the compound of theformula (IVa) by oxidizing a compound having the formula (Va)

under oxidizing conditions.
 5. The method of claim 4, wherein the methodfurther comprises formation of the compound of the formula (Va) byreacting a compound having the formula WCO₂R₄ and a compound having theformula (Via)

wherein W is halogen.
 6. The method of claim 4, wherein the oxidizingconditions are an electrochemical oxidation.
 7. A method of making acompound having the formula (Ib)

wherein R₁ is carboxy, amino, deuterium, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆) alkynyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, nitro,nitro(C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkyl-S(O)_(m), R₁₅R₁₆NS(O)_(m), R₁₅R₁₆NS(O)_(m) (C₁-C₆)alkyl,R₁₅S(O)_(m) R₁₆N, R₁₅S(O)_(m)R₁₆N(C₁-C₆)alkyl or a group of the formula(VII)

R₂ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl, or(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, nitro,(C₂-C₆)alkenyl, or (C₂-C₆)alkynyl; or R₂ is (C₃-C₁₀)cycloalkyl whereinthe cycloalkyl group is optionally substituted by deuterium, hydroxy,amino, trifluoromethyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,trifluoromethyl(C₁-C₆)alkyl, nitro, or nitro(C₁-C₆)alkyl; R₃ ishydrogen, (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl, (C₂-C₆)alkenyl, or(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, trifluoromethyl(C₁-C₆)alkyl, nitro, ornitro(C₁-C₆)alkyl; R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are each independentlyhydrogen or (C₁-C₆)alkyl optionally substituted by deuterium, hydroxy,amino, trifluoromethyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,trifluoromethyl(C₁-C₆)alkyl, nitro, or nitro(C₁-C₆)alkyl; R₁₂ iscarboxy, amino, deuterium, hydroxy, trifluoromethyl, (C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂ amino, amino(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(m),(C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl, R₁₅R₁₆NS(O)_(m), R₁₅R₁₆NS(O)_(m)(C₁-C₆)alkyl, or R₁₅S(O)_(m) R₁₆N, or R₁₅S(O)_(m)R₁₆N(C₁-C₆)alkyl; R₁₃is (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₆-C₁₀)aryl, (C₁-C₆)carboalkoxy,(C₅-Cg)heteroaryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl, or(C₅-Cg)heteroaryl(C₁-C₆)alkyl wherein the R₁₃ group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)alkyl,(C₁-C₄)alkoxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, trifluoromethyl(C₁-C₆)alkyl, nitro, ornitro(C₁-C₆)alkyl; R₁₅ and R₁₆ are each independently hydrogen or(C₁-C₆)alkyl; X is S(O)_(p); Y is S(O)_(p); Z is S(O)_(p); a is 0, 1, 2,3 or 4; b, c, e, f and g are each independently 0 or 1; d is 0, 1, 2, or3; m is 0, 1 or 2; n is 1, 2, 3, or 4; p is 0, 1 or 2; and wherein themethod comprises reducing a compound of formula (IIb).

with a reducing agent, wherein R₁₄ is (C₁-C₆)alkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₆)alkenyl, or (C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynylgroups are optionally substituted by deuterium, hydroxy, halogen, amino,trifluoromethyl, (C₁-C₄)alkoxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, trifluoromethyl(C₁-C₆)alkyl, nitro, ornitro(C₁-C₆)alkyl.
 8. The method of claim 7, wherein the method furthercomprises formation of the compound of the formula (IIb) by reacting acompound having the formula (IIIb)

with an aldehyde of formula R₁₃—(C═O)—H and reducing the compound soformed with a reducing agent.
 9. The method of claim 8, wherein themethod further comprises formation of the compound of the formula (IIIb)by hydrogenating a compound having the formula (IVb)

in the presence of a catalyst.
 10. The method of claim 9, wherein themethod further comprises formation of the compound of the formula (IVb)by reacting a compound having the formula (Vb)

with (R₁₄—O—(C═O))20 or R₁₄—O—(C═O)—X wherein X is halo.
 11. The methodof claim 1, wherein the compound of formula (Ia) has the relativestereochemistry of formula (Ia-1)

R₁ is (C₁-C₆)alkyl; n is one; R₂ and R₃ are each hydrogen or(C₁-C₆)alkyl; and R₄ is (C₁-C₆)alkyl.
 12. The method of claim 7, whereinthe compound of formula (Ib) has the relative stereochemistry of formula(Ib-1)

R₁ is (C₁-C₆)alkyl; n is one; R₂ and R₃ are each hydrogen or(C₁-C₆)alkyl; and R₁₃ is (C₆-C₁₀)aryl.
 13. The method of claim 1,wherein the reducing agent is a borohydride.
 14. The method of claim 7,wherein the reducing agent is lithium aluminum hydride.
 15. The methodof claim 9, wherein the catalyst is Rh/alumina or Rh/C.